In collaboration with Dr. W.H. Sawyer, Professor of Pharmacology, Coll. of Physicians and Surgeons of Columbia Univ., New York, we can report the first discovery of in vivo antagonists of the antidiuretic effects of both exogenous and endogenous arginine vasopressin (AVP). Such compounds have been sought for over 25 years in these and in other laboratories. These antagonists were designed by modifying the highly active and selective antidiuretic agonist (1-deamino, 4-valine, 8-D-arginine)vasopressin (dVDAVP) at positions 1,2 & 8. Analogs 1-4: X equals Me, Et, iPr, nPr; Y equals D-Arg. Analogs 5-8: X equals Me, Et, iPr, nPr; Y equals L-Arg. All eight analogs cause a transient antidiuresis when injected i.v. into rats and effectively antagonize antidiuretic responses to subsequent injections of AVP. They exhibit the following anti-antidiuretic pA2 values: (1) 6.68; (2) 7.10; (3) 6.88; (4) 6.60; (5) 7.35; (6) 7.57; (7) 7.32; (8) 7.29. Thus analog (6) is the most potent of these antagonists. These antagonists are potentially useful pharmacological tools for studies on the roles of AVP in regulating water balance in normal and pathophysiological states in animals and in humans. They may also have clinical value for the treatment of hyponatremia secondary to the inappropriate secretion of AVP. They also serve as excellent lead compounds for the design of even more potent and selective antidiuretic antagonists. This project summary contained formulas, drawings, tables or nonkeyable data which are not shown above.